JP2006528648A - Preparation and use of alkylating agents - Google Patents

Abstract

  The present disclosure provides methods for the synthesis and use of alkylating agents.

Description

Cross-reference to related applications This application is continuing, as of the filing date of 35 USC 119 (e) of US Patent Application No. 60 / 490,233, filed July 24, 2003, which is expressly included as a reference. Insist on the interests of.
The present invention relates generally to organic chemistry, and more particularly to methods of synthesis and use of alkylating agents.

Alkylation methods have been used to synthesize and modify a large number of compounds (eg, US Pat. Nos. 6,279,792, 6,780,820, 6,281,380, 6,281,399, 6,281,405, No. 6288233, No. 6291716, No. 6291724, No. 6294499, No. 6303840, No. 6307048, No. 6313362, No. 6315964, No. 6339179, No. 6355839, No. 6376729, No. 6376730, No. 6387705, No. 6388157, No. 6392114, No. 6395871, No. 6395945, No. 6343871, No. 6429349, No. 6440886, No. 6448458, No. 6647721, No. 6486374, No. 6649571, No. 6500998, No. 6650401, No. 6512153, No. 6515169, No. No. 6541655, No. 6548113, No. 6552421, No. 6557222, No. 6462425, No. 6642426, No. 6664342, No. 6667377, No. 6677269, No. No. 6747152 No. 6750354, No. 6759349). These methods typically require multi-step synthesis and purification of reaction intermediates and / or removal of unwanted by-products. Therefore, these methods synthesize or modify radiolabeled compounds, particularly when the radioisotope has a relatively short lifetime and the radiolabeled compound is intended for use as a radiotracer or imaging agent. May be unsuitable or may be restricted in use. Thus, there is a need in the art for a rapid and effective alkylation method that can be used to synthesize or modify radiolabeled compounds.
Therefore, the present disclosure provides compositions and methods for the rapid and effective alkylation of target compounds that can be used in the synthesis or modification of radiopharmaceuticals.

The present disclosure provides a method for alkylating a target compound comprising one or more alkylating reactive groups. In some embodiments, the method includes synthesizing an alkylating agent. In certain embodiments, the alkylating agent may include one or more leaving groups and an alkylating moiety. In certain optional embodiments, the alkylating agent may include a detectable moiety. In certain embodiments, the alkylating moiety may include a detectable moiety. In certain embodiments, the detectable moiety may be a radioisotope.
In some embodiments, the alkylating agent can be utilized in the alkylation reaction without an intervening purification step. Thus, in certain embodiments, alkylating agents can be used to directly alkylate target compounds once synthesized. In certain embodiments, synthesis of the alkylating agent and alkylation of the target compound can occur in a single vessel.
In certain embodiments, various aspects of the disclosed methods can be automated by general purpose or special purpose devices. In certain embodiments, the apparatus may include a processor or computer for storing data and / or executing computer program code instructions. Thus, in some embodiments, computer readable memory may be utilized to guide the computer to function in a particular manner. A computer or processor may control any one or more aspects of the disclosed methods.
In other aspects of the disclosure, alkylated and / or labeled target compounds are provided. In certain embodiments, the target compound may be labeled with a radioactive detectable moiety. Thus, in certain embodiments, alkylated and / or labeled target compounds can be used as therapeutic agents, tracers, and / or in vitro or in vivo imaging agents. In certain embodiments, the labeled target compound can be used as an imaging agent for positron emission tomography.

The present disclosure relates to the discovery of methods for synthesizing alkylating agents and methods for alkylating target compounds. In certain embodiments, the alkylating agent can be labeled. In certain embodiments, the label can be transferred to the target compound in an alkylation reaction. In certain embodiments, the alkylated target compound has application as a tracer molecule, imaging agent or therapeutic agent. Thus, in certain embodiments, the labeled alkylated target compound may be a radiopharmaceutical that can be used to measure the metabolic or physiological state of a cell or tissue in vivo or in vitro. Thus, in certain embodiments, the present disclosure provides a method for detecting or monitoring radioactive compounds in tissue or cells. In certain embodiments, the radioactive compound to be detected or monitored can be used to assess the metabolic or physiological state of a cell or tissue.
In certain embodiments, the disclosed methods include synthesis of alkylating agents and alkylation of target compounds in a single reaction vessel. In certain embodiments, the synthesis and alkylation reaction may be a paired operation without an intervening purification step. In certain embodiments, these methods further comprise isolating or purifying the alkylated target compound.
In certain embodiments, one or more aspects of the disclosed method can be automated. Thus, in various embodiments, the disclosure provides one or more automated modules, each capable of performing and / or providing reaction conditions suitable for one or more steps of the disclosed method. In some embodiments, one or more modules may be controlled by a device having a processor for storing data and / or commands.

“Alkylating agents” and grammatical equivalents herein are moieties suitable for generating an alkyl group that can be transferred to another compound in an alkylation reaction, for example, an alkylation reactive center or group of a target compound. Represents a compound having As used herein, “alkylation reactions”, “alkylating”, “alkylation” and grammatical equivalents transfer an alkyl group to an alkylation reactive center or group of a compound by substitution and / or addition. It means reaction. Thus, in certain embodiments, the alkyl group can be transferred to the alkylation reactive center of the target compound to produce an alkylated target compound. The “alkylation reactive center”, “alkylation reactive group” and grammatical equivalents herein are at least one of the compounds that react with the alkylating agent in such a way that the alkyl group can be transferred from the alkylating agent to the compound. Means one atom. In certain embodiments, “alkyl groups” and grammatical equivalents herein represent any of a series of monovalent groups of the general formula C _n H _{(2n + 1)} . Thus, in various exemplary embodiments, the alkyl group may be methyl, ethyl, propyl, isopropyl, C ₂ H _3, etc., or as further described below. In certain embodiments, the alkyl group may further comprise a detectable moiety.
In various exemplary embodiments, the alkylation reaction is nucleophilic at the alkylation reactive center of the target compound to the electron-deficient region of the alkylating agent via the SN ₁ or SN ₂ mechanism, as known in the art. Attacks may be included (see, for example, Advanced Organic Chemistry: Reactions, Mechanism, and Structure. 293-871 by Jerry March (Vol. 4, John Wiley & Sons 1992)). Thus, those skilled in the art will recognize that in certain embodiments, the alkylating agent further comprises one or more leaving groups (LG). As used herein, “leaving group” and grammatical equivalents refer to an atom or molecule that separates from a molecule, eg, an organic molecule. In certain embodiments, the remaining moiety may be an alkyl group that becomes covalently attached to the target compound. Thus, in various exemplary embodiments, the leaving group is charged or uncharged, which becomes separated from atoms or molecules in what is considered the residual or major portion of the substrate in a particular reaction. It may be an atom or a group. The ability of the leaving group to leave the alkylating agent can be a function of the leaving group instability. Thus, the leaving group can affect the intrinsic reactivity of the alkylating agent in the alkylation reaction. In some embodiments, the lower the pKa of the conjugate acid of the leaving group, the better the leaving group. This is because in some embodiments, the leaving group can more easily stabilize the negative charge that may occur in the alkylation reaction. Thus, in certain embodiments, the leaving group may be an electronegative atom or molecule. Examples of leaving groups include acetate (AcO), p-nitrobenzoate (PNBO), sulfonate (eg, methanesulfonate (mesylate: MsO), p-toluenesulfonate (tosylate: TsO), p-bromobenzenesulfonate (brosylate: BsO), p-nitrobenzenesulfonate (nosylate: NsO), fluoromethanesulfonate, difluoromethanesulfonate, trifluoromethanesulfonate (triflate: TfO) and ethanesulfonate), NH ₃ , halide esters, halogen ions (eg, I ⁻ , Br ^-, Cl ^-) and H ₂ but O include, but are not limited to. Therefore, in various exemplary embodiments, as the alkylating agent, (TsO) ₂ CH ₂ , (TsO) CH ₃ , (TsO) ₂ C ₂ H ₅ , (TsO) ₂ C ₃ H ₇ , (MsO) _{C 2 H 5, (I)} 2 CH 2, (I) CH 3, (I) 2 C 2 H 5, (I) 2 C 3 H 7, (I) C 2 H 5, (Br) 2 CH 2 , (Br) CH ₃ , (Br) ₂ C ₂ H ₅ , (Br) ₂ C ₃ H ₇ , (Br) C ₂ H _{5 and the} like, but are not limited thereto.

In certain embodiments, the alkylating agent includes one or more labels. In certain embodiments, a group or moiety suitable for transfer to a target compound (ie, an alkylating moiety) includes one or more labels. As used herein, “label”, “detectable moiety”, and grammatical equivalents refer to any distinguishable feature of a molecule or compound suitable for detection or monitoring. Thus, the label may be a characteristic of the compound and / or a moiety that is covalently or non-covalently attached to the compound. Labels are well known in the art and are selected at the discretion of the expert based on how the compounds containing the label are synthesized, used and / or detected. One skilled in the art will recognize that in certain embodiments, the label does not substantially interfere with or inhibit the function or activity of the compound comprising the label. Thus, in certain embodiments, the label of the alkylating agent may not substantially interfere with the alkylation of another compound, eg, the target compound, by the alkylating agent. It is within the ability of one skilled in the art to determine the extent to which a label can interfere with the activity or function of a compound to which it can bind.
In various exemplary embodiments, the label may be a fluorophore (eg, Richard P. Haugland, explicitly included by reference, Handbook of Fluorescent Probes and Research Chemicals 6th edition (Michelle TA Spence, edited by Molecular Probes, Inc. 1996)); ligands (eg, haptens, biotin), mobility improvers (eg, US Pat. Nos. 5,470,705, 5,145,543, 6,395,486) clearly incorporated by reference, encoded microbeads ( For example, U.S. Pat. Nos. 6,630,307, 6500622, 6,6274323), enzyme labels, organic or inorganic compounds, radioactive labels (eg, ¹⁸ F, ¹¹ C, ¹⁴ C, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ⁷⁶ Br), or a combination thereof. In certain embodiments, it is preferred that the radiolabel has a high specific activity, eg, at least about 600 mCi / mmol or more and / or a short positron range, eg, from about 2 mm to about 5 mm. In some embodiments, the location range may be less than about 2 mm. Thus, in certain embodiments, the radioactive label may be a positron emitter suitable for radioimaging techniques, including but not limited to positron emission tomography (PET).

In certain embodiments, the alkylating agent has a structure of Formula I and includes an alkylating moiety, a leaving group, and a label.
X- (CR ¹ R ² ) _a CR ³ R ⁴ -LG (I)
Where
a is an integer from 0 to 3,
R ¹ , R ² , R ³ and R ⁴ are independently H, X or alkyl;
X is H, halogen or a label, and
LG is a leaving group.
In some embodiments,
a is 1,
R ¹ , R ² , R ³ , and R ⁴ are H;
X is ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I or ⁷⁶ Br, and
LG is a sulfonate ester.
In some embodiments,
a is 0,
R ³ and R ⁴ are H,
X is [ ¹⁸ F], and
LG is tosylate, mesylate or triflate.

In some embodiments,
a is 0,
R ³ and R ⁴ are H or X,
X is [ ¹⁸ F], and
LG is tosylate, mesylate or triflate.
Thus, in various exemplary embodiments, alkylating agents that include a radiolabel include haloalkyl sulfonates such as [ ¹⁸ F] fluoroalkyl sulfonate (eg, [ ¹⁸ F] fluoroethane sulfonate (eg, [ ¹⁸ F] fluoro Ethanetosylate, [ ¹⁸ F] fluoroethane mesylate, [ ¹⁸ F] fluorotriflate), [ ¹⁸ F] fluoromethanesulfonate (eg, [ ¹⁸ F] fluoromethane tosylate, [ ¹⁸ F] fluoromethane mesylate, [ ¹⁸ F] fluoromethane triflate)), [ ⁷⁶ B] bromoalkyl sulfonate (eg, [ ⁷⁶ B] bromoethane sulfonate (eg, [ ⁷⁶ B] bromoethane tosylate, [ ⁷⁶ B] bromoethane mesylate, [ ⁷⁶ B] bromoethane triflate), ^[76 B] bromo methanesulfonate (eg , ^[76 B] bromo methane tosylate, ^[76 B] bromo methane mesylate, ^[76 B] bromo methane triflate)), ^[125 I] iodo alkyl sulfonates (e.g., ^[125 I] iodo-ethane sulfonate (e.g., [ ¹²⁵ I] iodoethane tosylate, [ ¹²⁵ I] iodoethane mesylate, [ ¹²⁵ I] iodoethane triflate), [ ¹²⁵ I] iodomethane sulfonate (eg, [ ¹²⁵ I] iodomethane tosylate, [ ¹²⁵ I ] Iodomethane mesylate, [ ¹²⁵ I] iodomethane triflate)), and the like.
In various exemplary embodiments, alkylating agents find use in methods of alkylating or labeling target compounds. As used herein, “target compound” and grammatical equivalents refer to a compound that contains one or more alkylation reactive centers, and thus can be used alone or in any combination, according to the methods disclosed herein. Alkylation is possible with the above alkylating agents. In certain embodiments, two or more target compounds may be alkylated simultaneously and / or sequentially with one or more alkylating agents. Determining the suitability of one or more target compounds or one or more alkylation reactive centers for alkylation with one or more alkylating agents simultaneously or sequentially is within the ability of one skilled in the art. In certain embodiments, the target compound comprises a label as described above. Thus, in certain embodiments, the label does not substantially interfere with or inhibit the use of alkylated and / or alkylated target compounds.

  In certain embodiments, the alkylation reactive center or group of the target compound may be a nucleophile suitable for the alkylation reaction. Examples of alkylation reactive centers include N, O, S, P, C, aldehyde, aliphatic carbon, alkane, alkene, alkyne, alcohol (—OH), amine (eg, primary amine, secondary amine, tertiary Amines and quaternary amines), aromatic compounds (eg, benzene, phenol), carboxylic acids (-COOH), esters, diazonium ions, dithianes, enamines, enolates, heterocycles, hydrazones, imines, ketones, nitriles, oxazines, oxazolines , Selenium oxides, sulfones, sulfonates, and cyclic, linear, and branched, substituted and unsubstituted derivatives thereof. The Dictionary of Chemical Terms (edited by Parker et al., McGraw-Hill Book Co.), Encyclopedia of Chemistry (edited by Considine et al., Volume 4, Van Nostrand Reinhold Co.), March, Advanced Organic Chemistry) are clearly included for reference. See In certain embodiments, the alkylating reactive group is alkyl, substituted alkyl, saturated and unsaturated cycloalkyl, aryl, substituted aryl, sulfhydryl (-SH), amino, and, for example, nitrogen, oxygen, sulfur, and the like Saturated and unsaturated heterocycles containing one or more of the combinations may be used.

As used herein, an “alkyl group” is a saturated or unsaturated, branched, linear or cyclic 1 derived by removal of one hydrogen atom or leaving group from a single carbon atom of a parent alkane, alkene or alkyne. Means a valent hydrocarbon group. If branched, it may be branched at one or more locations and unless otherwise specified. Typical alkyl groups include methyl; ethyl, such as ethanyl, ethenyl, ethynyl; propyl, such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1- Yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl, cycloprop-2-en-1-yl, prop-1-in -1-yl, prop-2-yn-1-yl, etc .; butyl, such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2- Yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1- Yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1- En-3-yl, cyclobuta-1,3-dien-1-yl, but-1-in-1-yl, 1-yn-3-yl, but but-3-yn-1-yl, and the like, without limitation.
Thus, in certain embodiments, an “alkyl group” is a group having any degree or level of saturation, ie, a group having exclusively a single carbon-carbon bond, one or more double carbon-carbon bonds. Groups, groups having one or more triple carbon-carbon bonds and groups having a mixture of single carbon-carbon bonds, double carbon-carbon bonds and triple carbon-carbon bonds. Where special levels of saturation are intended, the expressions “alkanyl”, “alkenyl”, and “alkynyl” are used. In various exemplary embodiments, the alkyl group has from about 1 to about 20 carbon atoms (C ₁ -C ₂₀ alkyl), from about 1 to about 15 carbon atoms (C ₁ -C ₁₅ alkyl). From about 1 to about 10 carbon atoms (C ₁ -C ₁₀ alkyl), or from about 1 to about 6 carbon atoms (C ₁ -C ₆ alkyl), or from about 1 to about 3 Up to carbon atoms (C ₁ -C ₃ ).

The term “substituted alkyl group” means that one or more hydrogen atoms are substituted, eg, halide (eg, F, Br, I, Cl), alkyl, amine, aromatic, aryl, hydroxyl, carbonyl, diazo, imine Represents an alkyl group as defined above, which is substituted by nitrile, nitro, sulfhydryl and sulfonyl.
The term “cycloalkyl group” refers to an alkyl group as defined above having a cyclic structure having up to about 20 carbon atoms (C ₂₀ ). In various exemplary embodiments, the cycloalkyl may be monocyclic or polycyclic, eg, bicyclic. A cycloalkyl group may optionally contain one or more carbon-carbon double bonds, provided that the group is not aromatic. Thus, in various exemplary embodiments, the cycloalkyl group can be saturated or unsaturated.
As used herein, an “aryl group” refers to about 6 to about 20 carbon atoms (C ₆ -C ₂₀ aryl), about 6 to about 15 carbon atoms (C ₆ -C ₁₅ aryl) ) Or aromatic monocyclic or polycyclic hydrocarbon groups containing from about 6 to about 10 carbon atoms (C ₆ -C ₁₀ aryl) and any of these carbocyclic ketones or thioketone derivatives Carbon atoms having different valences are members of an aromatic ring (eg aryl, phenyl, naphthyl, anthracenyl, phenanthrenyl, 1,2,3,4-tetrahydro-5-naphthyl, 1-oxo-1,2 -Dihydro-5-naphthyl, 1-thioxo-1,2-dihydro-5-naphthyl and the like).
In certain embodiments, aryl may be heteroaryl. A “heteroaryl group” is an aromatic monocyclic or polycyclic hydrocarbon group containing a total of 6 to 20 atoms (at least 1 to about 5 of the indicated carbon atoms being N, O, Substituted by a heteroatom selected from S, P or As, the atom having a free valence is a member of an aromatic ring, and their heterocyclic ketones and thioketone derivatives (eg thienyl, furyl, pyrrolyl) , Pyrimidinyl, isoxazolyl, oxazolyl, indolyl, benzo [b] thienyl, isobenzofuranyl, purinyl, isoquinolyl, pteridinyl, pyrimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, 4-oxo-1,2-dihydro-1-naphthyl, 4-thioxo-1,2-dihydro-1-naphthyl and the like. Thus, examples of hetero (C ₆ ) aryl include a pyridyl group and a pyrimidinyl group.

In certain embodiments, aryl may be substituted aryl. “Substituted aryl group” is a group in which one or more hydrogen atoms are substituted, for example, halide (eg, F, Br, I, Cl), alkyl, amine, aromatic compound, aryl, hydroxyl, carbonyl, diazo, imine, nitrile Represents an aryl group as defined above, which is substituted by nitro, sulfhydryl and sulfonyl.
As used herein, “heterocycle” refers to a ring containing more than one atom. Thus, in certain embodiments, heterocycles include, but are not limited to, carbocycles having at least one other atom in the ring. In various exemplary embodiments, the heterocycle may be saturated or unsaturated. In certain embodiments, heteroatoms can be attached to the ring structure. In certain embodiments, the heterocycle may have up to 20 atoms in one or more rings. Thus, in various exemplary embodiments, the heterocycle may be monocyclic or polycyclic, eg, bicyclic.
Thus, in various exemplary embodiments, the target compound is an organic compound, an inorganic compound, a naturally occurring compound (eg, isolated from nature) (eg, a polypeptide, nucleic acid, hormone, cytokine, antibody, etc.), non-naturally occurring. Production compounds (eg, synthetic or naturally occurring, eg, peptide nucleic acids (PNA)), pharmaceuticals (eg, antiviral drugs, prodrugs) and / or combinations thereof may be included. In certain embodiments, the target compound may be a biological compound. As used herein, “biological compound”, “biochemical compound” and grammatical equivalents are at least one in vivo (eg, in a subject) or in vitro (eg, in a tissue culture medium or assay). It means a compound having biological or biochemical activity. Thus, in various exemplary embodiments, the biologically active compound may specifically or non-specifically bind to another molecule and / or cell and / or enter the cell concerned. Also good. In certain embodiments, the cells may be prokaryotic cells, eukaryotic cells (eg, tumor cells), blood cells, anucleated cells, enucleated cells, and the like. In various exemplary embodiments, the binding may be to a molecule (eg, an antibody or binding fragment thereof), a class of molecule (eg, an MHC class II molecule), a specific receptor or a class of receptor, etc. . In certain embodiments, it is preferred that the biologically active compound crosses one or more cell membranes and / or cell walls. In certain embodiments, the biologically active compound may accumulate in an organ or region of the cell (eg, cytoplasm, mitochondria, endoplasmic reticulum, one or more surfaces of the membrane, etc.). Biologically active compounds may enter cells by various mechanisms, such as active or passive mechanisms. These mechanisms include, but are not limited to, diffusion mechanisms and food and drink mechanisms, such as receptor-mediated endocytosis, and active and passive transport. In certain embodiments, the biologically active compound is absorbed by the associated cells at a rate or size that substantially exceeds other cells. Thus, the present disclosure provides biologically active compounds that invade involved cells at a rate that exceeds other cells and biologically active compounds that accumulate in related cells at final concentrations that exceed concentrations in other cells. Intended for compounds. For example, in certain embodiments, biological compounds can preferentially enter tumor cells compared to non-tumor cells.

  In certain embodiments, after entering the cell, the biologically active compound can be metabolized by the cell, thereby changing the hydrophobicity of the biologically active compound. In certain embodiments, the hydrophobicity of the biologically active compound is reduced once modified to promote retention of the compound in the cell. The hydrophobicity of a biologically active compound can be determined by some cellular processes, such as oxidation (eg, conversion of the hydroxyl group to carbonyl), or removal of hydrophobic groups (eg, alkyl), polar groups (eg, May be reduced by the addition of hydroxyl) or charged groups (eg phosphates, carboxylates). Methods by which the hydrophobicity of biologically active compounds can be reduced are within the ability of one skilled in the art and can be based on the biologically active compounds and the metabolic processes of the cells involved.

  Examples of biologically active compounds include choline, dimethylethanolamine (DeGrado et al. (2001) J. Nucl. Med. (42: 1805-1814); US Pat. No. 6630125; Hara et al. (2002) J. Nucl Med. 43 (2): 187-199; Hara et al. Patent Office, Patent Journal (A), Published Patent Application 1997 (1997) No. 48747), Morphine, Heroin, Petine, Tamoxifen, Codeine, Nicotine Thioproperazine, diazepam, caffeine, flunitrazepam, hexamethonium, methiodide, quinuclidinyl benzylate, glucose, deoxyglucose, lactic acid, hexobarbital, thymidine, iodoantipyrine, antipyrine, coenzyme Q, adenosylmethionine, Phenylamine (Huang et al. (2002) Nuc. Med. Biol. 29 (741-751)), CP-126,998 (Musachio et al. (2002) Nucl. Med. Biol. 29: 547-552), cocaine derivatives (Schonbachler et al. ( 2002) Nuc l Med. Biol. 29: 19-27), proteins and peptides (US Pat. No. 6,358,489), neurokinin-1 receptor antagonists (US Pat. Nos. 6,241,964, 6,187,284), spiroperidol (US Inv. Reg. H1209, US Pat. No. 4,871,527), fatty acids (US Pat. No. 6,362,352), platelet GPIIb / IIIa receptor antagonists (US Pat. Nos. 5,879,657, 6022523), fluoromisonazole (US Pat. No. 5,886,190) ), Tamoxifen derivatives (US Pat. No. 5,215,548), opioid ligands (US Pat. No. 4,775,759; Ravert et al. (2002) Nucl. Med. Biol. 29: 47-53; Ogawa et al. (2001) Nucl. Med. Biol. 28) : 941-947), non-steroidal aromatic compounds (US Pat. No. 6019957), amino acid analogs (US Pat. Nos. 5,187,766 and 5,808,146), MQNB, neostigmine, MPP, NMS, amino acids (eg tyrosine (eg , -OH), serine (eg, -OH), threo Nin (eg -OH), cysteine (eg thio), aspartic acid (eg -COOH), glutamic acid (eg -COOH)), carboxylic acids (eg benzoic acid and amino acids), spiperone, spiroperidol For example, but not limited to.

Alkylating agents can be synthesized from disubstituted alkyl precursors. Thus, in certain embodiments, the precursor of the alkylating agent may have the structure of Formula II.
LG ^1- (CR ¹ R ² ) _a CR ³ R ⁴ -LG ² (II)
Where
a is 0-2,
R ¹ , R ² , R ³ and R ⁴ are independently H, labeled, CH ₃ , C ₂ H ₃ , and
LG ¹ and LG ² are leaving groups.
In some embodiments,
a is 0 to 1,
R ¹ , R ² , R ³ and R ⁴ are H, and
LG ¹ and LG ² are sulfonate esters or ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ⁷⁶ Br.
In some embodiments,
a is 0 to 1,
R ¹ , R ² , R ³ and R ⁴ are H, and
LG ¹ and LG ² are independently tosylate, mesylate or triflate.
In some embodiments,
a is 1,
R ¹ , R ² , R ³ and R ⁴ are H, and
LG ¹ and LG ² are both tosylate, mesylate or triflate.
In some embodiments,
a is 0,
R ³ and R ⁴ are H, and
LG ¹ and LG ² are both tosylate, mesylate or triflate.

Thus, in various exemplary embodiments, precursors of alkylating agents include, but are not limited to, disulfonic acid esters such as ditosylethane, dimesylethane, ditrifluorethane, ditosylmethane, dimesylmethane, and ditrifrylmethane.
In some embodiments, the alkylating agent may be synthesized by halogenating its precursor. In certain embodiments, the halogen may be a radioisotope (eg, ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, ⁷⁶ Br) and therefore may be a label. In a preferred embodiment, the halogen may be ¹⁸ F. In some embodiments, ¹⁸ F may be [ ¹⁸ F] fluoride and may be produced by several methods as are known in the art. In one embodiment, ¹⁸ F is irradiated with [ ¹⁸ O] H ₂ O with high energy protons in a cyclotron to produce [ ¹⁸ F] HF / [ ¹⁸ O] H ₂ O as known in the art. 400 that can be manufactured by manufacturing. In certain embodiments, [ ¹⁸ F] fluoride may be purified by chromatography, including but not limited to ion exchange chromatography 410 and other methods as are known in the art.
Other methods for producing radioisotopes are known in the art (eg, Handbook of Radiopharmaceuticals (Welch and Radvanly, John Wiley & Sons, 2003) and Chemists' View of Imaging Centers 291-295 (Emran, See Penum Press 1995)). For example, methods for the production of iodine radionuclides are described in Finn, Chemistry Applied to Iodine Radionuclides and Chemists' View of Imaging Centers 291-295 (Emran in Handbook of Radiophamaceuticals 423-400 (Welch and Redvanly edited, John Wiley & Sons, 2003). Edit, Penum Press 1995), in Washburn et al., Production and Application of ¹²³ I-Labeled M-Iodobenzylguanidine ( ¹²³ I-MIBG). A method for producing bromo radionuclides can be found in Rowland et al., Radiobromine for Imaging and Therapy 441-465 in Handbook of Radiophamaceuticals 423-400 (Welch and Redvanly, John Wiley & Sons, 2003).

In certain embodiments, the halogenation of the precursor may be as described by Block et al., 1987, J. Label. Compds. Radiopharm. 24: 1029-41. However, in certain embodiments, the temperature of the halogenation reaction can be important in determining the yield of the alkylating agent. Thus, in various exemplary embodiments, the temperature of the halogenation reaction is from about 40 ° C. to 80 ° C., from about 40 ° C. to about 50 ° C., from about 45 ° C. to about 50 ° C., or from about 20 ° C. to about It may be up to 50 ° C. In general, without being bound by theory, when alkylating precursors are halogenated, the alkylating agents synthesized include but are not limited to dihaloalkanes that react with halogens rather than precursors that occur in the synthesis of by-products. Can be sex. Thus, low temperatures (eg, below about 50 ° C.) can reduce byproduct synthesis. One skilled in the art will recognize that low temperatures reduce the rate of the halogenation reaction. Thus, in certain embodiments where the halogen is a radioisotope, the temperature and rate of the reaction can be adjusted to minimize the extent of radioisotope decay during the reaction. Determination of the optimum temperature and rate range for the halogenation reaction is within the ability of one skilled in the art. However, in some embodiments, a temperature of about 40 ° C. or less may be unsuitable when the radioisotope has a half-life of about 2 hours or less. In some embodiments, the halogenation comprises Cryptoflix® (eg, Cryptoflix® 2.2.2) or a basic tetraalkylammonium salt (eg, tetrabutylammonium bicarbonate), including Without limitation, this can occur in the presence of a catalyst 410. In some embodiments, potassium carbonate can provide a counterion for halide ions, such as [ ¹⁸ F] fluoride ions. However, the choice of source and type of counter ion is within the ability of one skilled in the art and can be influenced by the type of halide ion and / or target compound chosen at the discretion of the expert. In some embodiments, the halogenation reaction includes any means including, but not limited to, shaking, mixing, and blowing a substantially inert gas (eg, argon, nitrogen, helium, etc.) into the reaction. Can be stirred by 450. In some embodiments, stirring can be maintained as long as possible during the reaction.

In various exemplary embodiments, a solid support or resin can be used to minimize or inhibit the synthesis of dihaloalkyl by-products. In some embodiments, the solid support or resin binds to halide ions that can be used to halogenate the precursor. In some embodiments, the alkylating agent precursor may be a disulfonic acid ester as described above. In some embodiments, the resin may be a polymer resin comprising a covalently bonded quaternary ammonium salt (eg, a quaternary 4-dialkylaminopyridinium salt), eg, polystyrene (FIG. 12). In some embodiments, the solid support may be QMA.
In some embodiments, the purified halide ions, such as [ ¹⁸ F] fluoride ions, comprise azeotropic drying 420 and cooling 430 under a stream of argon at a temperature of at least about 110 ° C. to at least about 115 ° C. However, it can be dried using methods such as, but not limited to, those known in the art. In some embodiments, the azeotropic drying temperature may be higher or lower than this range, but those skilled in the art will understand the synthesis of the alkylating agent and the downstream use of the alkylating agent rather than the actual temperature at which drying occurs. The effect of drying on the suitability of halide ions for will be recognized.
Once made, the alkylating agent may be used to alkylate or label the target compound 460 in certain embodiments, with or without purification. As used herein, “purification”, “purify”, and grammatical equivalents mean to reduce the amount of foreign matter, such as by-products, from the material concerned. Thus, in certain embodiments, the alkylating agent, once made, can be used directly to alkylate or label the target compound. In certain embodiments, the target compound can be added directly to the container used to synthesize the alkylating agent. Thus, in some embodiments, the alkylating agent and the alkylated target compound may be prepared in a paired reaction (in some embodiments, it may be a “one pot, two step” operation). .

In certain embodiments, the amount of target compound may be liquid at the beginning of the alkylation reaction and may be from about 0.2 mL to about 0.5 mL. In certain embodiments, the target compound may be used neat. In certain embodiments, the target compound may be diluted or dissolved in a solvent including but not limited to acetonitrile, dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and tetrahydrofuran (THF). The choice of solvent type for use with the target compound is within the ability of one skilled in the art. In various exemplary embodiments, the alkylation of the target compound is about 100 ° C., about 100 ° C. to about 130 ° C., or about 100 ° C. to about 110 ° C., or about 100 ° C. for about 10 to about 25 minutes. It can occur up to about 105 ° C. and can be stirred as described above 460. The selection of temperature and reaction period is within the ability of one skilled in the art.
In certain embodiments, the target compound is alkylated according to Scheme 1.
Scheme 1
LG- (CH ₂ ) _n R ⁵ + Q _m Z → Q _m Z (CH ₂ ) _n R ⁵
Where
n is an integer from 1 to 3,
R ⁵ is H or a label (X),
LG is a leaving group,
Q _m Z is the alkylation reactive center of the target compound, m is an integer of 1-4, and each Q is independently H, alkyl, substituted alkyl, cycloalkyl, aryl and substituted aryl groups; Z is N, O, S, P or C.
In some embodiments,
n is an integer from 1 to 2,
R ⁵ is a label (X),
LG is a sulfonate ester,
Q _m Z is the alkylation reactive center of the target compound, m is an integer of 1-4, and each Q is independently H, alkyl, substituted alkyl, cycloalkyl, aryl and substituted aryl, Z Is N, O, S, P or C.

In some embodiments,
n is an integer from 1 to 2,
X is a radioactive label,
LG is mesylate, tosylate or triflate,
Q _m Z is the alkylation reactive center of the target compound, m is an integer of 1-3, and each Q _1-3 is independently methyl and hydroxyethyl, and Z is N.
Once the target compound is alkylated or labeled, in certain embodiments it can be purified by various means as is known in the art. For example, the alkylated target compound can be purified by electrophoresis, precipitation, extraction, and / or column chromatography 470 (eg, ion exchange chromatography, molecular exclusion chromatography). The determination of any one or more purification steps or methods for purifying an alkylated or labeled target compound is within the ability of one skilled in the art. Thus, those skilled in the art will appreciate that, for example, chromatographic alkylation or purification of a labeled target compound can include one or more washing steps 480, 490 prior to elution 500. In certain embodiments, the pH or ionic strength of the alkylated or labeled target compound may subsequently change 510. In certain embodiments, the alkylated or labeled target compound may be purified such that it is suitable for use in a living subject 520.
For purposes of illustration and not limitation, alkylated target compounds are N-fluoromethyl-MQNB (FIG. 4), N-fluoromethyl-MPP (FIG. 6), N-fluoromethylspiperone (FNMS), [ ¹⁸ F] fluoromethyl-neostigmine, [ ¹⁸ F] fluoromethyl-tyrosine and 3- (2′-fluoroethyl) spiperone (FESP) may be used. In certain embodiments, the alkylated target compound can also be labeled. Thus, the present disclosure contemplates radiolabeled target compounds in certain embodiments. Thus, in various exemplary embodiments, the fluorine in each of the above can be replaced by ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I, or ⁷⁶ Br.
In certain embodiments, the alkylated target compound can have the structure of Formula III.

Where
R ′ is ¹⁸ F, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹³¹ I or ⁷⁶ Br;
B ^- is a counter ion,
b is an integer from 1 to 3,
R ⁶ , R ⁷ and R ¹⁰ are independently CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₆ H ₅ ,
R ⁸ and R ⁹ are independently H, CH ₃ , or C ₂ H ₅ .
Thus, in various exemplary embodiments, the alkylated labeled compound is a choline analog (eg, N, N-dimethyl-N-fluoromethylethanolamine (fluorocholine: FCH), N, N-dimethyl-N -Fluoroethylethanolamine (fluoroethylcholine: FECh), [ ¹⁸ F] FCH, and [ ¹⁸ F] FECh, N, N-dimethyl-N-bromomethylethanolamine (bromocholine: BrCH), N, N-dimethyl- N- bromoethyl ethanolamine (bromoethyl choline: BrECh), ^[76 Br] BrCH, and ^[76 Br] BrECh, N, N- dimethyl -N- iodo-methylethanolamine (Yodokorin: ICH), N, N- dimethyl -N-iodoethylethanolamine (iodoethylcholine: IECh), [ ¹²⁵ I] ICH, [ ¹²⁵ I] IECh, and the like may be used.
In certain other embodiments, the alkylated compound may be other than, for example, [ ¹⁸ F] FCH, [ ¹⁸ F] FECh or [ ¹⁸ F] FDG (fluorodeoxyglucose). The alkylating agent used to prepare the compound is purified prior to the alkylation reaction.

In one embodiment, the method for producing [ ¹⁸ F] -labeled target compound (T _c ) comprises adding [ ¹⁸ F] fluoride and X— (CH ₂ ) _n —X to a reaction vessel and adding [ ¹⁸ F] — (CH ₂ ) _n -X (wherein X is tosylate, mesylate or triflate and n is 1-4), and a target compound containing an alkylating reactive group is added to the reaction vessel. Te ^[18 F] - (CH _{2) n} -T _c generates, the reaction mixture through a first chromatographic support ^[18 F] - (CH ₂₎ combining the _n -T _c, ^[18 Eluting F]-(CH ₂ ) _n -T _c from the support. In certain embodiments, the reaction vessel may be in liquid communication with the first chromatography support. In some embodiments, the first chromatographic support has an outlet in liquid communication with a distributor for delivering an aliquot of [ ¹⁸ F]-(CH ₂ ) _n -T _c eluent to individual vials. Have. In certain embodiments, the second chromatography support may be in liquid communication with and located between the first chromatography support and the distributor.
Once made, alkylated or labeled target compounds (target compound derivatives) may have in vivo or in vitro uses at the discretion of the skilled artisan. In certain embodiments, an alkylated or labeled target compound can be used to modify or label a second target compound. As illustrated in FIG. 13, a labeled amino acid can be attached to the peptide. In certain embodiments, the method of conjugation is described, for example, by Bianco et al., 2003, Org. Biomol. Chem. 1 (23): 4141-3 (Epub Oct. 22, 2003); Deechongkit et al., 2004, Org Lett. 6 (4): 497-500; Hojo et al., 2004, Chem. Pharm. Bull. (Tokyo) 52 (4): 422-7; Malkinson et al., Org. Lett. 5 (26): 5051-4; Merrifield, 1995, Biopolymers 37 (1): 3-4; Merrifield, 1997, Methods Enzymol. 289: 3-13; Song et al., 2004, Bioorg. Med. Chem. Lett. 14 (1): 161-5; Stephenson et al., 2004, Bioconjug. Chem. 15 (1): 128-36; Wang et al., 1987, Int. J. Pept. Protein Res. 30 (5): 662-667, and U.S. Patent Nos. 4507230, 4816513, Solid-phase peptide synthesis methods such as those described in US Pat. Nos. 5,186,898, 5,230,304, 5,258,454, 5,268,468, 5,380,495, and 5,444,150 can be used.

In certain embodiments, the labeled target compound may have use as a therapeutic agent, imaging agent, radiopharmaceutical, or tracer. Thus, in certain embodiments, alkylated or labeled target compounds can be used to detect, monitor or analyze a subject's cells or tissues. In certain embodiments, the cells or tissues may be benign, malignant, neoplastic and / or cancer and may be staged by imaging techniques. In certain embodiments, the imaging technique may be positron emission tomography (PET). Methods and techniques for performing PET are known in the art (eg, US Pat. Nos. 4,456,582, 4,624,464, 4,477,79, 4,677,299, 4,473,383, 4,864,138, 4864140, 5027817, 5103098, 5138165, 5210420, 5224037, 5224037, 5319204, 5378893, 5543623, 5591977, No. 5602395, No. 5574802, No. 5827499, No. 5987992, No. 6130430, No. 6288399, No. 6434216, No. 6521893, No. 6668803, No. ) Thus, in certain embodiments, alkylated or labeled target compounds can be formulated according to their intended use at the discretion of the expert. For use as an in vivo imaging agent, the labeled target compound is formulated to be suitable for intravenous injection (eg, sterile, nonpyrogenic). In certain embodiments, the labeled target compound is formulated with a pharmaceutically acceptable carrier, such as a pharmaceutically acceptable salt, and a pharmaceutically effective amount is administered to the subject.
As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is made with a counterion, is generally accepted in the art for pharmaceutical use, and has the desired pharmacological activity of the parent compound. means. As such salts, (1) inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid , Pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid , Ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl Bicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauric Acid addition salts produced with sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc., or (2) acidic protons present in the parent compound are metal ions, such as alkali metal ions, Substituted with alkaline earth ions or aluminum ions, or produced when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc. Salt. Also included are salts of amino acids such as alginates and the like, and salts of organic acids such as glucuronic acid or galacturonic acid (see, eg, Berge et al., 1977, J. Pharm. Sci. 66: 1-19). thing).

A “pharmaceutically effective amount” or “therapeutically effective amount” is an amount sufficient to produce a desired physiological effect or in particular a reduction or elimination of one or more symptoms of a disorder or disease or prevention of a disease or condition or The amount capable of obtaining a desired effect for diagnosing or treating a symptom is represented. Thus, in a preferred embodiment, the labeled target compound can be administered in an amount sufficient to detect, monitor and / or stage a tumor in the subject. The amount to be administered and the route of administration are chosen at the discretion of the expert as is known in the art.
Aqueous and non-aqueous isotonic sterile injection solutions (eg, formulations suitable for parenteral administration, such as by intraarterial (in joint), intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes) These may include antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient), and aqueous and non-aqueous sterile suspensions (these are suspensions) , May include solubilizers, thickeners, stabilizers, and preservatives). In the practice of the invention, the composition may be administered, for example, by intravenous infusion, oral, topical, intraperitoneal, intravesical or intrathecal. Parenteral administration, oral administration, subcutaneous administration and intravenous administration are the preferred methods of administration.

In various exemplary embodiments, the above methods of synthesizing alkylating agents, alkylation or labeling of target compounds, and / or purification of alkylated or labeled target compounds can be automated. Thus, in certain embodiments, the disclosed methods may be implemented on general purpose or special purpose devices, such as devices having a processor for storing data and / or commands. The computing device may be a single computer or a plurality of networked computers, and some operations associated with performing the methods and operations described herein may be one or more computer devices. It will be appreciated that it can be implemented. In some embodiments, the disclosed operations and methods are implemented on a normal server-client network infrastructure including various embodiments of the disclosed features that are added to or compatible with the infrastructure. The methods, processes and operations described herein may generally be implemented in software, hardware and / or combinations thereof. In some embodiments, such as illustrated in FIG. 10, processor 300 is indicated by a readable memory 310. In some embodiments, the processor 300 may be programmed to direct the purification of halogen ions, eg, [ ¹⁸ F] fluoride ions 100 using QMA 170. In one embodiment, processor 300 directs the elution of [ ¹⁸ F] fluoride 100 from QMA 170 using K222 / carbonate 110 and directs the eluate to reaction vessel (RV) 210. In some embodiments, ditosylmethane 120 may be directed to reaction vessel 210. To synthesize an alkylating agent such as [ ¹⁸ F] fluoromethane tosylate, the processor 300 instructs the temperature control module 320 to heat the reaction vessel 210 to a programmed temperature chosen at the discretion of the expert. For example, the mixed reactants can be induced by blowing an inert gas such as argon 180. In some embodiments, processor 300 directs the addition of dimethylamine 130 to RV 210, which is heated by thermal control module 320 and mixed with argon 180 to alkylate or label the target compound, eg, [ ¹⁸ F ] FCH can be synthesized. EtOH / water 140 is directed to the reaction vessel 320 by the processor 300, which in one embodiment cleans the reaction vessel 320 to obtain additional alkylation product. In some embodiments, the processor 300 directs the contents of the reaction vessel 320 to the silica column 200. Waste 230 does not bind to silica column 200, and in certain embodiments, alkylated products, such as [ ¹⁸ F] FCH, can be eluted by AcOH 150. AcOH 150 is removed by directing the eluate to weakly basic ion exchange resin 240 and the alkylated product, eg, [ ¹⁸ F] FCH, is collected in vial 250. Valve 160 controls inflow into and out of QMA 170. Three-way valves 190 and 220 control the flow into and / or out of the silica column 200, waste 230, weakly basic ion exchange resin 240 and vial 250.

In some embodiments, these methods and operations are automated by the insertion of three-way valves 190 and 220, as shown, in a Siemens-CTI chemical process control unit (CPCU) (CTI, Knoxville, TN). Can do. As is known in the art, CPCU has three components: a chemical process control unit, a control chassis, an operating system and control software designed to be programmable by an expert to direct various operations. Have As is known in the art, the CPCU includes an IBM compatible PC system and a standard (STD) bus subsystem. The computer operates with Microsoft® Windows NT® operating system and Intel® software package (eg, [ ¹⁸ F] Chemical Process Control Unit (CHF.SA 10.0796.0500, CTI, Inc. , 1996); and Padgett et al., 1989, “Computer-controlled radiochemical synthesis: a chemical process unit for the automated production of radiopharmaceuticals” Int. J. Rad. Appl. Instrum [A]. 40 (5): 433-45 checking).
As used in this specification and claims, the single forms “a”, “an”, and “the” include the plural unless the context clearly indicates otherwise. The following examples are presented for purposes of illustration and not limitation. Thus, it is understood that these examples cannot be used to limit the true scope of this disclosure. All references cited herein, including patents and / or patent applications cited in the technical field, cross-references of related applications, are included herein by reference.

Reagents and solvents were obtained from Aldrich Chemical Company and Fisher Scientific and used without further purification unless otherwise stated. The melting point is recorded with Electrothermal 9100 (Electrothermal Engineering, Southend-on-Sea, UK) and not corrected. NMR spectroscopy was performed on a Varian 400 MHz instrument (Varian, Palo Alto, Calif.). Column chromatography was performed on 230 mesh silica gel (catalog number 4791010, Whatman, Clifton, NJ). Thin layer chromatography (TLC) was performed on a silica 60F ₂₅₄ analytical plate (E. Merck, catalog number 4410222, Whatman, Clifton, NJ) equipped with a Bioscan 200 imaging scanner (Bioscan, Washington, DC). A UV detector in series with high pressure liquid chromatography (HPLC) (see, eg, FIGS. 15 and 17) (Catalog No. WAT080690, Waters Corporation, Milford, Mass.) And a radioactivity detector (eg, (See Figures 14 and 16) Performed on a Waters 600 system (Waters Corporation, Milford, Mass.) Equipped with (Catalog Number FC3200, Bioscan, Washington, DC), Pertisil SCX column (250x4.6mm, catalog) No. 8173, All-Tech Associates, Deerfield, IL) was eluted with 20% acetonitrile / water solution containing 0.25 mol / L sodium dihydrogen phosphate at 1 mL / min. Hewlett-Packard 6890GC (Hewlett-Packard, Palo Alto) equipped with a gas chromatography (GC) CAM column (30 mm x 0.25 μm, catalog number 1122132, J & W Scientific, Agilent Technologies, Palo Alto, CA) , CA).

Example 1 Ditosylmethane was prepared by mixing ditosylmethane diiodomethane (1.2 g, 4.5 mmol) and 2 × p-toluenesulfonic acid silver salt (2.8 g, 11 mmol) in anhydrous acetonitrile (20 mL). The resulting mixture was refluxed for 16 hours. Ditosylmethane was purified using a 230 mesh silica gel column (Cat. No. 4791010, Whatman, Clifton, NJ) (30-40% ethyl acetate-hexane) to give a white crystalline product (1 g, 63%) It was. Melting point 117 ° C (document melting point 116-117 ° C); ¹ H-NMR (CDCl ₃ , 400 MHz) δ 2.45 (s, 6H, CH ₃ ), 5.10 (s, 2H, OCH ₂ O), 7.25 (d, J = 8 Hz, 2H), 7.60 (d, J = 8 Hz, 2H)
Example 2: N, N-dimethyl-N-fluoromethylethanolamine (fluorocholine (FCH))
The sealed tube containing 10 mL anhydrous tetrahydrofuran (THF) and 2 mL (20 mmol) N, N-dimethylethanolamine was cooled at -78 ° C. Chlorofluoromethane (5.7 g, 70 mmol, catalog number 593-70-4, Synquest Loves, Alachua, FL) was bubbled into the cooled solution for 15 minutes. The mixture was gradually warmed to room temperature overnight. A white solid formed which was filtered, washed 3 times with cold (ca. 5 ° C.) THF and dried under vacuum. FCH was isolated as a hygroscopic white solid (0.5 g, 15%). ¹ H-NMR (D ₂ O, 400 MHz) δ 3.24 (s, 3H, CH ₃ ), 3.25 (s, 3H, CH ₃ ), 3.60-3.63 (m, 2H, CH ₂ ), 4.05-4.08 ( m, 2H, CH ₂ OH), 5.43 (bd, J = 4.5 Hz, 2H, CH ₂ F)

Example 3: [ ¹⁸ F] fluoromethane tosylate and [ ¹⁸ F] fluoroethane tosylate
1,1-, 1,2- and 1,3-no-carrier-added substituted alkane ^[18 F] fluorination Block et al. (1987) J. Label Compds Radiopharm 24 :.. 1029-1042 by systematically studied It had been. We reproduced the results of Block et al. In [ ¹⁸ F] fluorination of ditosylmethane and 1,2-ditosylethane. Both reactions were heated at 80 ° C. for 5 minutes and the product was analyzed by TLC. TLC was performed on silica 60F254 analytical plates (Catalog # 4410222, Whatman, Clifton, NJ) in 30% ethyl acetate / hexane. [ ¹⁸ F] fluoride was included in these studies to obtain a UV detectable moiety for quality control analysis.
[ ¹⁸ F] fluorination of 1,2-ditosylethane resulted in an 80% yield of [ ¹⁸ F] fluoroethanetosylate (FIG. 1). [ ¹⁸ F] [ ¹⁹ F] difluoroethane was not detected. Therefore, no electron withdrawing effect was observed due to [ ¹⁸ F] fluorine in the β-position. An 80% yield was obtained without stirring the reaction. Although [ ¹⁸ F] fluoroethanetosylate can be produced at lower temperatures, those skilled in the art will recognize that the yield decreases as the temperature decreases.
[ ¹⁸ F] fluorination of ditosylmethane produced two labeled products, [ ¹⁸ F] difluoromethane and [ ¹⁸ F] [ ¹⁹ F] difluoromethane tosylate under various conditions. At 80 ° C., the only product is produced, the by-product [ ¹⁸ F] [ ¹⁹ F] difluoromethane, which is not beneficial for the synthesis of [ ¹⁸ F] fluorocholine. In addition, some free, detectable [ ¹⁸ F] fluoride is not unusual, especially when the reaction cannot proceed to completion. As predicted by the work of Block et al., The yield of [ ¹⁸ F] fluoromethane tosylate was about 1% (FIG. 2). The low yield of [ ¹⁸ F] fluoromethane tosylate is the result of [ ¹⁸ F] fluoromethane tosylate being more reactive than ditosylmethane in the SN ₂ reaction due to the electron withdrawing effect of the α-position fluorine It may be. Obviously, due to the very low concentration of [ ¹⁸ F] fluoride detected after the reaction, [ ¹⁸ F] fluoromethane tosylate has undergone secondary fluorination with the [ ¹⁹ F] carrier present in the reaction vessel. May produce [ ¹⁸ F] [ ¹⁹ F] difluoromethane, a very volatile compound (boiling point = -52 ° C).
The inventors investigated the effect of temperature on the fluorination of ditosylmethane. When the reaction temperature is lowered to about 45-50 ° C., the production of [ ¹⁸ F] [ ¹⁹ F] difluoromethane is reduced and we are sufficient to synthesize [ ¹⁸ F] FCH (FIG. 2). An amount of [ ¹⁸ F] fluoromethane tosylate was obtained. Only small amounts of [ ¹⁸ F] [ ¹⁹ F] difluoromethane were detected at temperatures below about 40 ° C. for up to 20 minutes. However, the reaction rate may be unsuitable for radiosynthesis using slightly shorter-lived isotopes. At temperatures above about 50 ° C., the main reaction product was [ ¹⁸ F] [ ¹⁹ F] difluoromethane.
The fluorination process is also sensitive to agitation. At temperatures from about 40 ° C. to about 50 ° C. in the absence of agitation, the reaction produced a small amount of [ ¹⁸ F] [ ¹⁹ F] difluoromethane, but also a small amount of [ ¹⁸ F] fluoromethane tosylate. (About 10% yield). Implementation of [ ¹⁸ F] fluorination at temperatures ranging from about 40 ° C. to about 50 ° C. with stirring produces sufficient amounts of [ ¹⁸ F] fluoromethane tosylate to synthesize [ ¹⁸ F] FCH. (About 30% yield).

Example 4: [ ¹⁸ F] N, N-dimethyl-N-fluoromethylethanolamine ([ ¹⁸ F] FCH)
[ ¹⁸ F] FCH two-step reaction: fluorination of ditosylmethane with [ ¹⁸ F] fluoride, followed by modified Siemens-CTI chemical process control unit (CPCU, catalog number 3601037, CTI, Knoxville, TN) (Figure 10) Was prepared by an alkylation reaction with [ ¹⁸ F] fluoromethane tosylate and dimethylethanolamine. [ ¹⁸ F] FCH was purified using a silica Sep-Pak column (catalog number WAT023537, Waters Corporation, Milford, Mass.). The column was washed with ethanol and water to remove all impurities and [ ¹⁸ F] FCH was eluted with 2% acetic acid. Acetic acid was removed using an AG4-X4 weakly basic ion exchange resin column (143-3341, Bio-Rad Laboratories, Hercules, CA) (see AG4 instruction manual LIT207 Rev B, Bio-Rad) . A three-way slider valve, for example, a Teflon slider valve, was added to the CPCU for purification (FIG. 10). The software was improved to lower the temperature and to allow stirring for the labeling process.

To prepare [ ¹⁸ F] fluoride, concentrated ¹⁸ O-water was irradiated with 11 MeV protons (33 μA for 60 minutes). After bombardment, the target ¹⁸ F-HF / ¹⁸ O-water solution was transferred to an anion exchange QMA cartridge (carbonate form) (catalog number WAT054725, Waters Corporation, Milford, Mass.) Using Ar pressure. Carrier-free [ ¹⁸ F] fluoride was captured with a QMA cartridge and ¹⁸ O-water was recovered. [ ¹⁸ F] fluoride with 2.2 mM potassium carbonate (K ₂ CO ₃ ) and 40 mM Cryptofix® 2.2.2 (4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8.8.8] 1 mL of acetonitrile: water solution (19: 1) containing hexacosane, C ₁₈ H ₃₆ N ₂ O ₆ , catalog number 291110, Sigma-Aldrich, St. Louis, MO was eluted from the cartridge into the reaction vessel. The mixture was azeotropically dried under a stream of Ar at 110 ° C. for 4 minutes and cooled for about 60 seconds. Ditosylmethane (10 mg, 0.03 mM) in 1 ml of anhydrous acetonitrile was added to the dry residue. The mixture was heated at 45-50 ° C. for 5 minutes by intermittent Ar gas blowing (10 seconds every 20 seconds). Thereafter, 1 mL of acetonitrile containing 0.2 mL of N, N-dimethylethanolamine was added to the reaction vessel, and this was heated at 100 ° C. for 10 minutes by intermittent Ar gas blowing (15 seconds every 30 seconds) (FIG. 3). The entire mixture was loaded onto a SiO ₂ Sep-Pak cartridge (catalog number WAT023537, Waters Corporation, Milford, Mass.) And washed with ethanol (3 × 5 mL) and water (2 × 5 mL). Two three-way valves were used to redirect the stream to the final product vial. [ ¹⁸ F] FCH was released from the SiO ₂ Sep-Pak cartridge with 5 mL of 2% acetic acid followed by 5 mL of H ₂ O. Acetic acid is removed from the eluent by an AG4-X4 weakly basic ion exchange resin column (Cat. No. 143-3341, Bio-Rad Laboratories, Hercules, CA) (see AG4 instruction manual LIT207 Rev B, Bio-Rad) Stripped and the solution passed through a 0.2 μm membrane filter (Cat. No. SLGS V255F, Millipore, Billerica, Mass.) Into a sterile vial containing 0.5 ml of 23.4% sodium chloride concentrated solution. In addition, the SiO ₂ Sep-Pak cartridge was replaced with a pre-activated (1N HCl 10 mL) accelerator cartridge (catalog number WAT023531, Waters, Milford, Mass.) And [ ¹⁸ F] FCH was eluted with 10 mL of saline.
The results of the alkylation reaction showed that [ ¹⁸ F] fluoromethane tosylate reacted almost quantitatively with N, N-dimethylethanolamine in acetonitrile, yielding> 90% yield of [ ¹⁸ F] FCH. Indicated. The overall yield from the synthesis of [ ¹⁸ F] fluoromethane tosylate to [ ¹⁸ F] FCH is 20%, due to the formation of [ ¹⁸ F] [ ¹⁹ F] difluoromethane during the fluorination process. It may be. Total synthesis time was less than about 40 minutes (see Figures 16 and 17).

Example 5: N, N-dimethyl-N-fluoroethylethanolamine (fluoroethylcholine (FECh)) synthesis
1-Bromo-2-fluoroethane (1 g, 8 mmol) was dissolved in N, N-dimethylethanolamine (0.7 g, 8 mmol) and heated at 100 ° C. for 10 minutes. The resulting mixture was taken up in 10% ethanol / ethyl acetate. After removal of the solvent, FECh was obtained as a white solid (1.7 g, 100%). ¹ H-NMR spectra were indistinguishable from those reported by Hara et al., 2002, J. Nucl. Med. 43 (2): 187-199.
Example 6: [ ¹⁸ F] N, N-Dimethyl-N-fluoroethylethanolamine ([ ¹⁸ F] FECh) Synthesis Anhydrous [ ¹⁸ F] fluoride was obtained as described in Example 3 to obtain anhydrous acetonitrile. Reacted with 1,2-bis-ditosylethane (10 mg, 0.03 mmol) in 1 mL. The mixture was heated at 80 ° C. for 5 minutes by intermittent Ar gas blowing (10 seconds every 20 seconds). Thereafter, 0.3 mL of N, N-dimethylethanolamine neat was added to the reaction vessel, which was heated at 100 ° C. for 10 minutes by intermittent Ar gas blowing (15 seconds every 30 seconds). [ ¹⁸ F] FECh was purified from the reaction mixture as described in Example 3 using a silica gel Sep-Pak cartridge.
Alkylation with [ ¹⁸ F] fluoroethanetosylate in N, N-dimethylethanolamine neat gave a yield of only 50%. The overall yield of [ ¹⁸ F] FECh is also 50%, which is higher than the yield of [ ¹⁸ F] FCH (20%). This may be the result of [ ¹⁸ F] [ ¹⁹ F] difluoroethane by-product being produced very little or not during the fluorination process. As described above for [ ¹⁸ F] FCH, the total synthesis time was less than about 40 minutes (see FIGS. 14 and 15).

Example 7: ^[18 F] FCH and ^[18 F] FECh purified ^[18 F] FCH and ^[18 F] FECh is quaternized alkylamines, they may absorb strongly onto silica gel Sep-Pak cartridge (Mulholland (1999) J. Label Componds Radiopham. 42: Suppl. 1 s459-s461). [ ¹⁸ F] FCH and [ ¹⁸ F] FECh were securely held in a cartridge that allowed most impurities to be quickly removed to waste by ethanol elution. Elution of [ ¹⁸ F] FCH and [ ¹⁸ F] FECh with a 2% acetic acid solution and a weakly basic ion exchange resin (AG 4-X4, catalog number 140-4341, Bio-Rad Laboratories, Hercules, CA) Was used to neutralize.
The radiochemical purity of [ ¹⁸ F] FCH and [ ¹⁸ F] FECh was measured by HPLC (HPLC 600 system, Waters Corporation, Milford, MA) and TLC (Silica 60F254 analytical plate, Whatman, Clifton, NJ). [ ¹⁸ F] FCH and [ ¹⁸ F] FECh eluted from the HPLC column at 6.8 minutes and 7.5 minutes, respectively. Waters 600 system (Waters) with UV detector (Catalog number WAT080690, Waters Corporation, Milford, MA) and radioactivity detector (Catalog number FC3200, Bioscan, Washington, DC) with HPLC in series • 20% with 0.25 mol / L sodium dihydrogen phosphate using a Particill SCX column (250x4.6mm, catalog number 8173, Alltech Associates, Deerfield, IL) Eluting with 1 mL / min of acetonitrile / water solution. The residual amount of N, N-dimethylethanolamine in the final solution was analyzed by GC using a CAM column designed for amines (catalog number 1122132, Agilent Technologies, Palo Alto, CA). The few chemical contaminants detected by HPLC and GC were N, N-dimethylethanolamine (<0.5 mg per batch) and ethanol (<5 mg per batch).

In order to reduce N, N-dimethylethanolamine contamination, the silica gel Sep-Pak cartridge was replaced with an accelerator cartridge (Hara et al. (1997) J. Nucl. Med. 38 (6): 842-847). The accelerator cartridge was preconditioned with HCl and H ₂ O and the final product was eluted with saline solution. N, N-dimethylethanolamine was found to be <0.1 mg per batch in [ ¹⁸ F] FCH preparation. [ ¹⁸ F] FECh was not effectively purified using an accelerator cartridge, ie about half of [ ¹⁸ F] FECh was found in the waste fraction.
The final purified solution of [ ¹⁸ F] FCH and [ ¹⁸ F] FECh in saline was cultured for microorganisms for growth in 37 ° C. concentrated thioglycolate and 23 ° C. trypticase soy broth medium (1 mL). No growth was observed for 2 weeks. The final purified solution was shown to be pyrogen-free using standard methods for LAL (Charles River Labs Endosafe, Charleston, SC). A positive control is always included in the assay. [ ¹⁸ F] FCH is currently undergoing FDA-approved preliminary clinical IND safety studies in humans. To date, after about 50 tests, no adverse effects from the tested [ ¹⁸ F] fluorocholine have been observed.
TLC plates were pretreated in 2% acetic acid and air dried before use. The plate was eluted in 2% acetic acid. The R _f of [ ¹⁸ F] FCH and [ ¹⁸ F] FECh is 0.40, which is consistent with the HPLC results.

Example 8: Other alkylating agent, alkylation method and purification method
Alternative forms of tosylate leaving groups for the SN ₂ nucleophilic substitution reaction used to prepare alkylating agents [ ¹⁸ F] FCH and [ ¹⁸ F] FECh include halides and other sulfonate esters such as , Methanesulfonate (eg, mesylate), and trifluoromethanesulfonate (eg, triflate). However, maintaining the alkylating agent in solution decreases as the volatility of the alkylating agent increases. Therefore, by increasing the number of carbon atoms, the volatility can be reduced, so that the alkylating agent can remain in solution.
Labeling of 1,2-ditritylethane with [ ¹⁸ F] fluoride gives> 80% yield of [ ¹⁸ F] fluoroethane triflate. This is greater than the yield of [ ¹⁸ F] fluoroethanetosylate. This is because triflate is the most reactive among the three sulfonate esters (mesylate, tosylate, triflate). Furthermore, high yields are obtained in the alkylation step with N, N-dimethylethanolamine using triflate as the leaving group. Alkylation using 2- [ ¹⁸ F] fluoroethanetosylate and N, N-dimethylethanolamine gives a yield of 50% of [ ¹⁸ F] FECh. In contrast, 2- [ ¹⁸ F] fluoroethane triflate reacts with N, N-dimethylethanolamine to yield [ ¹⁸ F] FECh quantitatively. Thus, the overall yield of [ ¹⁸ F] FECh using 1,2-ditritylethane as the unlabeled precursor is> 70%.
As a result of our study of labeled ditosylmethane with [ ¹⁸ F] fluoride, secondary fluorination is activated by the electron withdrawing effect of α-positioned [ ¹⁸ F] fluorine resulting in the synthesis of difluoromethane. Therefore, one or more steps for delaying or preventing the second activated fluorination are beneficial. Polymeric resin supports containing covalently bonded quaternary ammonium salts (eg J. Labelled Cpd. Radiophamceuticals 26: 378-380 (1989), FIG. 12) or solid supports such as QMA were irradiated [ ¹⁸ O] Carrier-free [ ¹⁸ F] fluoride from H ₂ O and labeled ditosylmethane is retained. Although polymer resin processes may not be as effective as solution reactions, they retard or prevent the formation of [ ¹⁸ F] [ ¹⁹ F] difluoromethane.
Since alkylated sulfonate esters are more reactive than halide esters, [ ¹⁸ F] fluoromethane tosylate and [ ¹⁸ F] fluoroethane tosylate are suitable for on-column alkylation with N, N-dimethylethanolamine. Yes. The sulfonate ester is captured on a Sep-Pak C18 cartridge loaded with dimethylethanolamine. Thus, [ ¹⁸ F] fluoromethylation of N, N-dimethylethanolamine is made efficient and the alkylation process is faster.
Purification We have shown that [ ¹⁸ F] FCH purification was performed using silica gel or accelerator cartridges. However, [ ¹⁸ F] FECh was effectively purified on silica gel but not on the accelerator cartridge. This may be due to alkylation process conditions that require the use of undiluted (neat) N, N-dimethylethanolamine. For [ ¹⁸ F] FCH, alkylation occurs in the solvent acetonitrile. Therefore, before loading the [ ¹⁸ F] FECh reaction mixture into the accelerator cartridge, 1 mL of acetonitrile is added, which allows the [ ¹⁸ F] FECh to be retained on the accelerator cartridge to facilitate purification.

Example 9: Other [ ¹⁸ F] -labeled target compounds The disclosed method uses [ ¹¹ C] alkyl iodide-labeled target compounds for longer life halogens, eg, ¹⁸ F-labeled equivalent compounds Can be used to replace Therefore, [ ¹⁸ F] fluoroalkanesulfonate can be used for various N, O, S and C alkylations. Examples of quaternary amines that can be [ ¹⁸ F] fluoroalkylated by the disclosed methods include MQNB (3-quinuclidinyl benzylate derivative), muscarinic ligand (FIG. 5), acetylcholinesterase inhibitor neostigmine (FIG. 6) and The metabolite TMA-phenol is mentioned and the neurotoxin N-methyl-4-phenyl-pyridinium is labeled using this method. Secondary amines that can be [ ¹⁸ F] fluoromethylated according to the disclosed method include [ ¹⁸ F] N-methyl spiperone ([ ¹⁸ F] NMS) and 3- (2 ′-[ ¹⁸ F] fluoroethyl) spiperone ( [ ¹⁸ F] FESP) (FIG. 7). The O-alkylation reaction is used to methylate the amino acid tyrosine in the presence of dimethyl sulfoxide (DMSO) (FIG. 8). The carboxylic acid is alkylated as shown in FIG. The S-alkylation reaction is used to fluoromethylate the target compound of FIG.

1 illustrates the synthesis of an alkylating agent, [ ¹⁸ F] fluoroethanetosylate, according to one embodiment. FIG. 4 illustrates the synthesis of an alkylating agent, [ ¹⁸ F] fluoromethane tosylate, according to one embodiment. FIG. 4 shows [ ¹⁸ F] fluoroalkylation of dimethylethanolamine according to one embodiment. 1 shows the structure of an [ ¹⁸ F] fluoroalkylated quaternary amine, 3-quinuclidinyl benzylate (MQNB), in one embodiment. 1 shows the structure of an [ ¹⁸ F] fluoroalkylated quaternary amine, neostigmine, acetylcholinesterase inhibitor, according to one embodiment. 1 illustrates the structure of [ ¹⁸ F] fluoroalkylated quaternary amine, N-methyl-4-phenyl-pyridinium (MPP), neurotoxin, in one embodiment. FIG. 4 shows O-fluoroalkylation of tyrosine (Tyr) using [ ¹⁸ F] fluoromethyl tosylate in dimethyl sulfoxide (DMSO), according to one embodiment. Figure 2 illustrates O-fluoroalkylation of a carboxylic acid, benzoic acid, in one embodiment. FIG. 3 illustrates S-fluoroalkylation of benzyl mercaptan (α-toluenethiol) in one embodiment. 1 shows a schematic diagram illustrating a system suitable for automated synthesis of an alkylating agent, alkylation of a target compound (T _c ), and purification of the alkylated target compound, in one embodiment. FIG. 3 shows a process flow diagram for the synthesis of a radioalkylated target compound in one embodiment. The numbers on the left of the figure indicate the approximate time points of the illustrated synthesis. 1 illustrates the structure of a polymer resin comprising polystyrene quaternary ammonium salts, polystyrene 4-dialkylaminopyridinium, in one embodiment. In the figure, R ¹¹ and R ¹² are alkyl groups. Shows the binding of ^[18 F] labeled cysteine to generate a methionine ^[18 F] to the amino terminus of fluoroalkylation and peptides ^[18 F] labeled methionine embodiment. Figure 2 shows HPLC tracing (mV vs. min) of [ ¹⁸ F] FECh using a radioactivity detector, according to one embodiment. Tracing shows the main radioactivity peak, [ ¹⁸ F] FECh. Figure 2 shows HPLC tracing (absorbance units (AU) vs. time) of [ ¹⁸ F] FECh using an ultraviolet (UV) detector, according to one embodiment. Tracing shows the main peak, dimethylethanolamine, detectable by UV absorption. [ ¹⁸ F] FECh cannot be detected by UV absorption. Figure 2 shows HPLC tracing (mV vs. min) of [ ¹⁸ F] FCH using a radioactivity detector in one embodiment. Tracing shows the main radioactivity peak, [ ¹⁸ F] FCH. Figure 2 shows HPLC tracing (mV vs. min) of [ ¹⁸ F] FCH using a radioactivity detector in one embodiment. Tracing shows the main peak, dimethylethanolamine, detectable by UV absorption. [ ¹⁸ F] FCH cannot be detected by UV absorption.

Explanation of symbols

100- [ ¹⁸ F] fluoride ion 120-ditosylmethane 130-dimethylamine 140-EtOH / water 150-AcOH
160-valve 170-QMA
180-Argon 190, 220-3 way valve 200-Silica column 210-Reaction vessel 230-Waste 240-Weak basic ion exchange resin 250-Vial 300-Processor 310-Memory 320-Thermal module

Claims (35)

a) Formula:
X- (CR ¹ R ² ) _a CR ³ R ⁴ -LG
(Where
a is 0, 1, 2 or 3;
R ¹ , R ² , R ³ and R ⁴ are independently H, X or alkyl;
X is a halogen or a label provided that at least one X is a halogen,
LG is a leaving group)
Synthesizing an alkylating agent having
b) A method for alkylating a target compound, which comprises reacting the alkylating agent directly with the target compound under conditions suitable for alkylating the target compound containing an alkylating reactive group. The alkylating agent is of the formula
X-CH ₂ CH ₂ -LG
(Where
X is [ ¹⁸ F], and
LG is a sulfonate ester)
The method of claim 1, comprising: The alkylating agent is of the formula
X-CH ₂ -LG
(Where
X is [ ¹⁸ F], and
LG is a sulfonate ester)
The method of claim 1, comprising: The alkylating agent is of the formula
CH ₃ -CH ₂ (X) -CH ₂ -LG
(Where
X is [ ¹⁸ F], and
LG is a sulfonate ester)
The method of claim 1, comprising: The alkylating agent is of the formula
X-CH ₂ -CH ₂ -CH ₂ -LG
(Where
X is [ ¹⁸ F], and
LG is a sulfonate ester)
The method of claim 1, comprising: The method of claim 1, wherein the precursor of the alkylating agent has the formula LG- (CR ¹ R ² ) _a CR ³ R ⁴ -LG. The method of claim 1, wherein the precursor has the formula LG- (CH ₂ ) ₂ -LG. The process of claim 1 wherein a is 0 and R ³ and R ⁴ are alkyl.   9. A method according to claim 2, 3, 4, 5, 6, 7 or 8, wherein LG is selected from the group consisting of tosylate, mesylate or triflate ester.   The alkylating reactive group is alkyl, substituted alkyl, alcohol, carxylic acid, saturated cycloalkyl, unsaturated cycloalkyl, aryl, substituted aryl, saturated heterocyclic ring, unsaturated heterocyclic ring, sulfhydryl, amine, N, O, S or The method of claim 1 comprising C.   The target compound is morphine, heroin, petine, tamoxifen, codeine, nicotine, thioproperazine, diazepam, caffeine, flunitrazepam, hexamethonium, methiodide, quinuclidinyl benzilatum, MQNB, neostigmine, MPP, NMS, tyrosine, The method of claim 1, wherein the method is selected from the group consisting of spiperone and spiroperidol. The alkylated target compound is [ ¹⁸ F] -fluoromethyl-MQNB, [ ¹⁸ F] N-fluoromethyl-MPP, [ ¹⁸ F] FNMS, [ ¹⁸ F] fluoroethyl spiperone, [ ¹⁸ F] fluoromethyl-neostigmine , ^[18 F] fluoromethyl - tyrosine method of claim 11.   The method of claim 1, wherein the target compound is selected from the group consisting of glucose, lactic acid, hexobarbital, thymidine, iodoantipyrine, antipyrine, and coenzyme Q.   The method of claim 1, wherein the target compound is dimethylethanolamine. Alkylated target compound ^[18 F] N, an N- dimethyl -N- fluoromethyl ethanolamine method of claim 14, wherein. Alkylated target compound ^[18 F] N, an N- dimethyl -N- fluoroethyl ethanolamine method of claim 14, wherein. formula
X- (CR ¹ R ² ) _a CR ³ R ⁴ -LG
(Where
a is 0, 1, 2 or 3;
R ¹ , R ² , R ³ and R ⁴ are independently H, X or alkyl;
X is a halogen or a label provided that at least one X is a halogen,
LG is a leaving group)
Contacting the alkylated reagent with a target compound comprising an alkylation reactive group under conditions suitable for alkylation of the target compound, wherein the alkylated target compound is [ ¹⁸ F] FCH, [ ¹⁸ F] FECh or A method for synthesizing an ¹⁸ F-labeled target compound, which is other than [ ¹⁸ F] fluorodeoxyglucose.   18. The method of claim 17, wherein LG is a sulfonate ester.   19. The method of claim 18, wherein the sulfonate ester is selected from the group consisting of tosylate, mesylate and triflate ester.   The target compound is morphine, heroin, petine, tamoxifen, codeine, nicotine, thioproperazine, diazepam, caffeine, flunitrazepam, hexamethonium, methiodide, quinuclidinyl benzilatum, MQNB, neostigmine, MPP, NMS, tyrosine, 18. The method of claim 17, wherein the method is selected from the group consisting of spiperone and spiroperidol. The alkylated target compound is [ ¹⁸ F] -fluoromethyl-MQNB, [ ¹⁸ F] N-fluoromethyl-MPP, [ ¹⁸ F] FNMS, [ ¹⁸ F] fluoroethyl spiperone, [ ¹⁸ F] fluoromethyl-neostigmine , ^[18 F] fluoromethyl - tyrosine method of claim 20, wherein.   18. The method of claim 17, wherein the target compound is selected from the group consisting of glucose, lactic acid, hexobarbital, thymidine, iodoantipyrine, antipyrine and coenzyme Q. a) Formula:
¹⁸ F- (CH ₂ ) _a -LG
(Where
a is 1 or 2,
LG is a leaving group)
Synthesizing an alkylating agent having
b) A method for alkylating dimethylethanolamine, wherein the alkylating agent is reacted directly with dimethylethanolamine under conditions suitable for alkylating dimethylethanolamine. The alkylating agent is of the formula
¹⁸ F-CH ₂ CH ₂ -LG
(Where
LG is a sulfonate ester)
24. The method of claim 23, comprising: The alkylating agent is of the formula
¹⁸ F-CH ₂ -LG
(Where
LG is a sulfonate ester)
24. The method of claim 23, comprising: The precursor of the alkylating agent has the formula LG- (CH _{2) a} -LG, method of claim 23.   27. The method of claim 23, 24, 25 or 26, wherein LG is selected from the group consisting of tosylate, mesylate or triflate ester. The fluoroalkyl choline is ^[18 F] N, an N- dimethyl -N- fluoromethyl ethanolamine method of claim 23, wherein. The fluoroalkyl choline is ^[18 F] N, an N- dimethyl -N- fluoroethyl ethanolamine method of claim 23, wherein. a) Using halide ions and catalyst in the reaction vessel, the formula:
X- (CR ¹ R ² ) _a CR ³ R ⁴ -LG
(Where
a is an integer from 0 to 2,
R ¹ , R ² , R ³ and R ⁴ are independently H or X;
X is a halogen or a label provided that at least one X is a halogen,
LG is a leaving group)
Executable instructions for inducing a computer to control a synthesis module for synthesizing an alkylating agent having:
b) Deriving the computer to control the synthesis module to react directly with the target compound containing an alkylating reactive group under conditions suitable for alkylating the target compound in the reaction vessel A computer readable memory for guiding a computer to function in a particular manner, characterized in that it contains executable instructions.   c) further comprising executable instructions for directing the computer to control the synthesis module for binding the alkylated target compound to the first solid support, wherein the reaction vessel and the first solid support are in fluid communication. 32. The computer readable memory of claim 30, wherein:   32. The computer readable memory of claim 31, further comprising: d) executable instructions for directing the computer to control the synthesis module for eluting the alkylated target compound from the first solid support.   e) binding the eluted alkylated target compound to the second support (the first solid support and the second solid support are in fluid communication) and the alkylated target compound is the second solid support 35. The computer readable memory of claim 32, further comprising executable instructions for directing the computer to control the synthesis module for eluting from the body. 18. An ¹⁸ F-labeled target compound made according to the method of claim 1 or 17. [ ¹⁸ F] alkylmorphine, [ ¹⁸ F] alkyl heroin, [ ¹⁸ F] alkyl petin, [ ¹⁸ F] alkyl tamoxifen, [ ¹⁸ F] alkyl codeine, [ ¹⁸ F] alkyl nicotine, [ ¹⁸ F] alkyl thioproperazine, [ ¹⁸ F] alkyl diazepam, [ ¹⁸ F] alkyl caffeine, [ ¹⁸ F] alkyl flunitrazepam, [ ¹⁸ F] alkyl hexamethonium, [ ¹⁸ F] alkyl methiodide, [ ¹⁸ F] alkyl quinuclidinyl benzil [ ¹⁸ F] alkyl-MQNB, [ ¹⁸ F] alkyl neostigmine, [ ¹⁸ F] alkyl-MPP, [ ¹⁸ F] alkyl-NMS, [ ¹⁸ F] alkyl tyrosine, [ ¹⁸ F] alkyl spiperone, and [ ¹⁸ F] A composition comprising a compound selected from the group consisting of alkylspiroperidols.

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